This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Burnet's clonal selection theory, the reigning paradigm in immunology, dictates that antigen selects specific lymphocytes from a large repertoire of T and B cells and induces them to selectively proliferate. These activated lymphocytes facilitate rapid antigen clearance and, upon neutralization of the antigenic threat, they persist in the host as memory lymphocytes for a lifetime. Later in life, encounter with the same antigen induces massive proliferation of these memory lymphocytes and rapid clearance of the antigen. While this scheme holds true for most immune responses, the phenomenon of "original antigenic sin", first described in humans vaccinated against influenza virus, stands out as a paradox to Burnet's rules of B cell engagement (Fazekas de St and Webster, 1966a). This project seeks to understand B cell memory as it relates to original antigenic sin responses to both strains and subtypes of influenza virus. Since original antigenic sin can drastically dampen immune responses to newer strains of influenza it is critical to understand the fundamentals of this phenomenon as this has tremendous implications for influenza vaccine research particularly with pandemic influenza looming on the horizon. In order to investigate the mechanism of original antigenic sin we have immunized cohorts of mice with inactivated influenza viruses, and we continue to collect and analyze the data concerning their immune responses.